Polyol derivatives and uses thereof for pigmenting the skin

Abstract

The invention relates to a compound of the following formula I: formula (I) or one of the enantiomers, isomers or diastereoisomers of same, or a mixture thereof, wherein R is a linear or cyclic C3-C6 alkyl, comprising two hydroxyl functions, a linear or cyclic C3-C6 aldehyde, comprising two hydroxyl functions, or a linear or cyclic C3-C6 ketone, comprising two hydroxyl functions, and wherein R1 is a C1-C3 alkyl, or a salt, or a solvate thereof.

Description

[0001] Description

[0002] Title of the invention: Polyol-type derivatives and their uses

[0003] The invention relates to derivatives of perfumed compounds, and their uses, particularly in the cosmetic and therapeutic fields.

[0004] Melanins, the predominant polymers that constitute the main pigment of the skin and appendages of vertebrates, have the capacity to absorb ultraviolet light and thus prevent damage to DNA.

[0005] The skin contains epidermal components responsible for melanin synthesis (melanocytes) and its distribution (keratinocytes). Melanin biogenesis, called melanogenesis, occurs in melanosomes, a specialized organelle related to the lysosome, present in melanocytes. This complex process involves several steps and begins with the oxidation of the amino acid L-tyrosine. Once synthesized, melanin is transferred via cellular extensions (dendrites) from melanocytes to neighboring keratinocytes, the main cell type present in the epidermis (30-40 keratinocytes per 1 melanocyte).

[0006] Skin pigmentation is of great cultural and cosmetic importance and is considered desirable by many people. Nowadays, the most common method for darkening skin is tanning using either natural sunlight or specially designed ultraviolet rays (tanning lamps / beds). Given the increasing incidence of UV-induced skin cancer / damage, linked to the progressive depletion of the ozone layer or excessive sunbathing, alternative tanning methods are of great interest.

[0007] The first self-tanning lotion containing dihydroxyacetone (DHA) was marketed in 1945 in California. Since the 1960s, sunless tanning has grown in popularity, and chemists have devoted considerable time to developing self-tanning formulas that produce a unique, identical bronze skin color due to the formation of surface pigments. This coloring is in no way due to the production of natural skin pigments, melanins. Almost all self-tanning products currently available contain DHA as the active ingredient, which may or may not be combined with erythrulose, tyrosine derivatives, and, occasionally, a naphthoquinone. DHA is a sugar substitute that reacts with amino acids in the skin through the Maillard reaction, a process well known to food chemists that causes food to brown during manufacturing, storage, and cooking.Although DHA does not require UV exposure to trigger a color change, some studies show that DHA-treated skin is more sensitive to UV rays and generates a large amount of additional free radicals internally. Additionally, most sunless tanning products do not contain sunscreen. If a sunscreen is present, it will only be effective for a few hours. Self-tanner does not provide any significant UV protection. In addition to this lack of protective effect, DHA has an unpleasant odor once applied to the skin. The odor problem varies from person to person depending on body chemistry.

[0008] It is therefore necessary to properly regulate melanogenesis, as it is an extremely important aspect of skin characteristics and a response to environmental stresses. To date, apart from UV exposure, there are few, if any, reliable methods that stimulate melanin production in the skin to enable a natural tan and significant UV protection.

[0009] To this end, application WO2021260168 describes the use of compounds as self-tanning substances and corresponding tanning compositions. Among the proposed compounds, it is envisaged to use odorous compounds that lead to the perception of an amber olfactory note. Among them, Ambermax, which has the greatest self-tanning power but nevertheless less significant than the effect obtained by UV, and certain of its derivatives and in particular its methylated derivative which has lesser self-tanning capacities.

[0010] All these compounds therefore have odors (intrinsic odors of self-tanning products or odors generated following skin application and subsequent reactions, which represents a market accessibility problem and a barrier to consumer adoption). Therefore, there is still a need to provide compounds allowing tanning, without the disadvantages of odors, which is at least close or similar to the tan obtained with UV rays.

[0011] The present invention meets these needs.

[0012] One of the aims of the invention is to provide new compounds having a self-tanning effect similar or equivalent to the tanning effect obtained during exposure to the sun.

[0013] Another object of the invention is to provide a pharmaceutical or cosmetic composition for this purpose.

[0014] Yet another aim of the invention is to propose a therapeutic use of the new compounds, with the aim of preventing the harmful effects of the sun.

[0015] The invention relates to a compound of the following formula I: or one of its enantiomers, isomers or diastereoisomers, or a mixture thereof, where R is a linear or cyclic C3-C6 alkyl comprising two hydroxyl functions, a linear or cyclic C3-C6 aldehyde comprising two hydroxyl functions, or a linear or cyclic C3-C6 ketone comprising two hydroxyl functions, and where R1 is a C1-C3 alkyl, or a salt, or a solvate thereof.

[0016] The invention is based on the following surprising observation: when the Ambermax compound is modified so as to graft onto it a compound comprising at least two alcohol functions, not only does the compound lose its odorous properties which are undesirable in cosmetics or pharmaceuticals, but it also makes it possible to increase the pigmentation of the skin in a manner similar to or greater than the pigmentation obtained after exposure to the sun.

[0017] The compound according to the invention comprises a C=C double bond which can take two positions. Since it is not fixed, it is represented in formula I by the dotted lines.

[0018] The compound according to the invention is a compound of formula I, where R1 is a C1-C3 alkyl, i.e. one of the following alkyls: a methyl -CH3(C1), an ethyl -CH2-CH3 (C2) or a propyl - (CH2)2-CH3 or an isopropyl -CH2-(CH3)2(C3).

[0019] In formula I, R can be a C3-C6 alkyl, i.e. a C3, C4, C5 or C6 alkyl, comprising two alcohol or hydroxyl (-OH) functions. Thus, in the invention, if the alkyl R is C3, it could comprise two or three alcohol functions, if the alkyl is C4 it could comprise two, three or four alcohol functions, if the alkyl is C5 it could comprise two, three, four or five alcohol functions, and if the alkyl is C6 it could comprise two, three, four, five or six alcohol functions.

[0020] R may be C3 alkyl, i.e. propyl, C4 alkyl, i.e. butyl or isopropyl, C5 alkyl, i.e. pentyl, 1-methyl butyl, 2-methyl butyl, or 1,2-dimethyl propyl, or C6 alkyl, i.e. hexyl, 1-methyl propyl, 2-methyl propyl, 3-methyl propyl, or 1,2-dimethyl butyl.

[0021] It is also possible for R to be a cyclic C3-C6 alkyl. Also, without representing the at least two alcohol functions, R can, in a cyclic form, be represented by one of the following formulas:

[0022]

[0023] Still without taking into account the position of the at least two alcohol functions, R can also be an aldehyde: Again without taking into account the position of the at least two alcohol functions, R can also be a ketone

[0024] The C3-C6 aldehydes and ketones comprising two aforementioned alcohol functions can also be cyclic in whole or in part, and in particular in the form of acetals or hemiacetals.

[0025] As can be seen from formula I, the compound according to the invention contains many asymmetric carbons. Also, within the scope of the invention, it is considered that all isomers, enantiomers and diastereoisomers are covered. The compound according to the invention is understood in its pure form, but also in the form of a mixture, racemic or not, of two or more isomers.

[0026] Furthermore, the compound according to the invention may be in a pure, non-electrically charged form, or in a salt form, possibly associated with a counter anion or cation.

[0027] The compound according to the invention is further soluble, or in a solvated form. Compared to Ambermax which is soluble in apolar aprotic solvents, the compound according to the invention is compatible with a physiologically acceptable solution, in particular a practical solvent, a polar solvent, a saline solution or pure water.

[0028] Advantageously, the invention relates to the above-mentioned compound, wherein said compound is selected from the compound of formula Ia, Ib, Ic, Id, Ic, If, Ig and Ih, following:

[0029] where R is as defined above. The above-mentioned compounds of formula Ia to Ih represent the different compounds according to the invention where R1 has been defined, and where the C=C double bond has been positioned. Furthermore, R1 has been defined.

[0030] Advantageously, the invention relates to the above-mentioned compound, where R is a linear or cyclic C3-C6 alkyl comprising three hydroxyl functions, a linear or cyclic C3-C6 aldehyde comprising three hydroxyl functions, or a linear or cyclic C3-C6 ketone comprising three hydroxyl functions.

[0031] It is advantageous in the context of the invention that R comprises three alcohol functions, whether it is an alkyl, an aldehyde or a ketone. By "comprising three hydroxyl functions" is meant in the invention, three hydroxyl functions, four hydroxyl functions, five hydroxyl functions, six hydroxyl functions or more. Even more advantageously, the invention relates to the aforementioned compound, where R is glycerol, butane-1,2,3,4-tetrol, inositol, sorbitol or a C3-C6 sugar.

[0032] In the context of the invention, R can therefore be glycerol, of formula . The derivatization reaction is carried out via any of the hydroxyl functions.

[0033] R can be butane-1,2,3,4-tetrol of formula , regardless of its R or S isomers, or its isomers or diastereoisomers. The derivatization reaction is carried out via any of the hydroxyl functions.

[0034] R can be inositol of formula , and this whatever its myo- isomers

[0035] , scyllo-, muco-, D-chiro-, L-chiro-, neo-, allo-, epi- or cis-inositol. The derivatization reaction is carried out via any of the hydroxyl functions.

[0036] R can also be sorbitol of formula , regardless of its R or S isomers, or its isomers or diastereoisomers. The derivatization reaction is carried out via any of the hydroxyl functions.

[0037] R may also be a C3-C6 sugar, in its linear form, or a furanosic or pyranosic form. The L and D isomers of said sugars are also covered by the present invention.

[0038] The covered C3 sugars are the trioses, namely dihydroacetone and glyceraldehyde. The covered C4 sugars are the tetroses, namely erythrose, threose and erythrulose.

[0039] The C5 sugars are the pentoses, namely ribose and deoxyribose, arabinose, xylose, lyxose, ribulose and xylulose. The C6 sugars are the hexoses, namely allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose and tagadose, and the deoxyhexoses namely fucose and rhamnose.

[0040] The derivatization reaction is carried out via the hydroxyl function carried by the anomeric carbon 1 of tetroses, pentoses or hexoses.

[0041] Generically, the invention thus covers the following compounds:

[0042] [Table 1]

[0043]

[0044]

[0045]

[0046] For better understanding of the table, the lines read as follows: the indicated compound Ia has a corresponding R, this radical R taking any of the indicated isoforms. If R is a sugar, in this case the -O- bond is either of type a or p. For example: covers the following compounds: α-form D Glucopyranose β-form D Glucopyranose

[0047] a-form L Glucopyranose p-form L Glucopyranose form a D Glucofuranose form p D Glucofuranose form a L Glucofuranose form p L Glucofuranose

[0048] A person skilled in the art will therefore be able to understand from the table above all the formulas covered by the present invention. Even more advantageously, the invention relates to the above-mentioned compound, said compound being chosen from the following compounds:

[0049]

[0050] Even more advantageously, the invention relates to the aforementioned compound, where, when R is a C3-C6 sugar, said sugar may be substituted by a C3-C6 sugar. In this advantageous embodiment is in fact a diholoside, or a polyholoside. R will then be a sugar composed of two oses such as for example:

[0051] Trehalulose => Glucose α(1→1) Fructose

[0052] Sucrose => Glucose α(1→2) Fructose

[0053] Turanose => Glucose α(1→3) Fructose

[0054] Maltulose => Glucose α(1→4) Fructose

[0055] Leucrose => Glucose α(1→5) Fructose

[0056] Isomaltulose (Palatinose) => Glucose α(1→6) Fructose

[0057] Gentiobiulose => Glucose β(1— >6) Fructose

[0058] Mélibiose => Glucose α(1→6) Galactose4

[0059] Lactulose => Galactose β(1— >4) Fructoses

[0060] Lactose => Galactose β(1— >4) Glucose

[0061] Rutinose => Rhamnose α (1→6) GlucoseG

[0062] Inulobiose7 => Fructose β(1— >1) Fructose

[0063] 2 alpha-Mannobiose => Mannose α(1→2) Mannose

[0064] 3 alpha-Mannobiose => Mannose α(1→3) Mannose

[0065] Tréhalose => Glucose α(1→1)a Glucose

[0066] Kojibiose => Glucose α(1→2) Glucose

[0067] Nigerose (sakébiose) => Glucose α(1→3) Glucose

[0068] Maltose => Glucose α(1— >4) Glucose

[0069] Isomaltose => Glucose α (1→6) Glucose

[0070] Sophorose => Glucose β(1— >2) Glucose

[0071] Laminaribiose => Glucose β(1 — >3) Glucose Cellobiose => Glucose P(1 — >4) Glucose

[0072] Gentiobiose => Glucose P(1 — >6) Glucose

[0073] Even more advantageously, the invention relates to the above-mentioned compound, said compound being chosen from the following compounds: compos o es une ce o ose (P- - glucopyranoside(1^4)-D-galactopyranose), compound where R is lactose (PD-galactopyranoside(1^4)- D-galactopyranose). , compound where R is sucrose (a-D-glucopyranoside (1^2)-D-fructofuranose),

[0074] The bond of the sugar that is substituted is uniformly an α or β bond.

[0075] In another aspect, the invention relates to a composition comprising a compound as defined above, in association with a pharmaceutically or cosmetically acceptable, in particular dermatologically acceptable, vehicle.

[0076] In the invention, the terms "pharmaceutically or cosmetically acceptable vehicle" mean that the composition or components thereof are suitable for use in contact with human skin and / or mucous membranes without undue toxicity, incompatibility, instability, allergic response, or their equivalents.

[0077] The cosmetically acceptable vehicle may be chosen from water, allantoin, glycerin, methylpropanediol; this list is not exhaustive.

[0078] The cosmetic or dermatological composition may be in any form suitable for cosmetic or dermatological application. Advantageously, the composition is a composition for topical use. It may be, for example, a composition in a form chosen from the group comprising an oil-in-water or water-in-oil emulsion or a mixture of these emulsions. The cosmetic or dermatological composition may, for example, be in a form chosen from the group comprising an aqueous or hydroalcoholic gel, an aqueous or hydroalcoholic cream and an aqueous or hydroalcoholic lotion. These usable formulations are known in the state of the art by formulators.

[0079] The composition may be in a form selected from an ointment, cream, oil, milk, salve, powder, soaked pad, solution, gel, serum, balm, butter, lotion, suspension, soap or emulsion.

[0080] The compound according to the invention can be used in a cosmetic or dermatological composition alone or in combination with other biologically active ingredients and / or substances making it possible in particular to accompany the compound according to the invention, to constitute a particular formulation, to preserve the compound over time, this list not being exhaustive. In other words, it can be any basic product that can be found in conventional cosmetic or dermatological compositions. The pharmaceutical composition according to the invention may also contain inert additives or combinations of these additives, such as - wetting agents; - preservatives; - stabilizing agents; - humidity regulating agents; - pH regulating agents; - osmotic pressure modifying agents; - emulsifying agents; - UV-A and UV-B filters; - and antioxidants.

[0081] Of course, those skilled in the art will take care to choose the possible compound(s) to be added to these compositions and their respective quantities in such a way that the advantageous properties intrinsically attached to the present invention are not or are not substantially altered by the envisaged addition.

[0082] It is advantageously envisaged to provide a composition where the compound according to the invention is in a proportion of 0.00001 to 10% by mass relative to the total mass of the composition, preferably 0.00001 to 5% by mass relative to the total mass of the composition, preferably 0.00001 to 3% by mass relative to the total mass of the composition, preferably 0.00001 to 2% by mass relative to the total mass of the composition.

[0083] Advantageously, the composition is applied to the skin, in particular in the form of a cream or lotion, in an amount of between 0.0001 and 100 mg / cm2 / day of compound as defined previously.

[0084] The invention also relates to the compound as defined above, as a medicament.

[0085] The medicament according to the invention is in a form particularly suitable for application to the skin, such as, for example, and without limitation, a cream, an ointment, a gel, a lotion, but also a soaked cloth, or a patch. It may also be an oil, an emulsion of the oil-in-water (O / W) or water-in-oil (W / O) type, a mousse, a gel, a stick or a spray.

[0086] The invention further relates to a compound as defined above, or to a compound as defined above, for its use in protecting the human epidermis against damage caused by ultraviolet radiation.

[0087] To the extent that the compounds according to the invention enable the production of melanin, this melanin exerts a protective effect during exposure to the sun, and therefore limits or even prevents the undesirable effects of sun exposure: sunburn or solar erythema.

[0088] Similarly, the invention relates to the non-therapeutic cosmetic use of a compound as defined above, for protection against solar UV rays.

[0089] Also contemplated is a method of preventing damage caused by ultraviolet radiation, particularly solar radiation, comprising a step of applying to the skin of an individual an amount sufficiently effective to protect him from the aforementioned composition or the aforementioned compound.

[0090] The invention also relates to the compound as defined above, for skin pigmentation, in particular for pigmentation of depigmented or lightly pigmented skin.

[0091] In order to protect skin phototypes I or II, which are very sensitive to sun damage, it is possible to use the compounds according to the invention. Colored skin phototypes IV, V (or VI, but more anecdotally) can also get "sunburned". Therefore, it is advantageous to use the composition or compound according to the invention to also protect this type of skin, despite their richness in natural melanin.

[0092] In another aspect, the invention relates to the use of the above-mentioned composition or compound for skin pigmentation, or even tanning, particularly in the absence of sun.

[0093] Although white skin was for a long time considered a criterion of social elevation in Western societies, since the end of the twentieth century a "tanned" complexion has taken on a predominant societal dimension.

[0094] While it is easily possible to obtain a tanned complexion and therefore have a "healthy glow" in summer by exposing oneself to the sun, this is more difficult in winter, particularly in Western countries of Europe and North America. Also, coloring the skin is an alternative to this lack of sun, while maintaining the aesthetics of the tan as in the summer period. The use of the composition or compound according to the invention therefore makes it possible to remedy this problem and allow people wishing to have a nice complexion to appear tanned even in winter.

[0095] The use of the above-mentioned composition or compound is also contemplated for the pigmentation of the appendages. The appendages are integumentary productions derived from the ectoderm and characterized by a high rate of keratinization. In humans and within the scope of the invention, the main appendages are hair, body hair and nails.

[0096] Also, the invention envisages a use of the above-mentioned composition for coloring hair, or even body hair, with a view to browning it, in particular in the context of age-related canities or dekeratinization or for pathological reasons.

[0097] In another aspect, the invention relates to a non-therapeutic cosmetic method of tanning comprising the topical application of the aforementioned composition, or the aforementioned compound, to the skin.

[0098] Brief description of the figures

[0099] The invention will be better understood by reading the following examples and the following figures: [Fig. 1] Figure 1 is a schematic representation of the schedule of the study on skin explants carried out over 10 days. 0 to 10 represent the days of the study. The black square represents exposure to ultraviolet (UV) rays, the black triangle represents the application of the product according to the invention, and the inverted gray triangle represents the sampling of the explants.

[0100] [Fig. 2] Figure 2 represents the characterization of melania in the basal layer of the epidermis for the control tissues (A), treatment with the solvent alone after 10 days (B), treatment with UV after 10 days (C), and treatment after 10 days with compositions P1 (D), P2 (E) and P3 (F). The coloration scores are as follows: 1: very weak; 2: weak; 3: moderate; 4: fairly light, 5: light; 6: very light; 7: strong.

[0101] [Fig. 3] Figure 3 is a histogram representing the percentage of melanin-positive surface in the basal layer of the epidermis on day 10, after treatment with the solvent (A), with UV (B) or with solutions P1 (C), P2 (D) or P3 (E). The ordinate represents the percentage of surface (in %).

[0102] [Fig. 4] Figure 4 represents a histogram showing the number of tyrosinase-positive cells per centimeter of epidermis on day 10, after treatment with the solvent (A), with UV (B) or with solutions P1 (C), P2 (D) or P3 (E). The ordinate represents the number of positive cells.

[0103] [Fig. 5] Figure 5 is a photograph showing a skin explant stained by the Masson Fontana technique, showing the expression of melanin after 10 days following treatment with the solvent.

[0104] [Fig. 6] Figure 6 is a photograph showing a skin explant stained by the Masson Fontana technique, showing the expression of melanin after 10 days following treatment with composition P3.

[0105] [Fig. 7] Figure 7 is a photograph showing a skin explant stained by the Masson Fontana technique, showing the expression of melanin after 10 days following UV treatment.

[0106] Examples

[0107] Example (2-(2,2,7,7-Tetramethyl-5-tricyclo[6.2.1,0 1 ' 6 ]undec-4-enyl)propan-1 - yljmonoglyceryl ether (4)

[0108] 1 2

[0109] 3 4 Compound 4 was synthesized using methods described in the literature such as those collected in the review article by Sutter et al.; Chem. Rev. 2015; 115 (16); 8609-8651, and in particular the method described by Utata et al., J. Am. Oil Chem Soc.;1988; 65 (8); 1299-1302.

[0110] To a vigorously stirred mixture comprising alcohol 1 (1.0 mol), 48% aqueous sodium hydroxide solution (3.0 mol as sodium hydroxide), quaternary ammonium salt (0.05 mol) and hexane (1000 mL), epichlorohydrin (2.0 mol) was added dropwise over 30 minutes at room temperature. After the addition of epichlorohydrin was complete, the mixture was stirred vigorously at 40°C for 5 hours. The reaction mixture was cooled, and the organic layer was separated and then dried over MgSCU. After filtration, intermediate 2 was obtained by evaporation of the organic solvents under reduced pressure and then used as such in the next step.

[0111] In a mixture of acetone (12 mol) and boron trifluoroetherate (0.05 mol), glycidyl ether (2) (1 mol) was gradually added. The resulting solution was stirred for another two hours and treated with aqueous sodium bicarbonate solution (0.1 mol). The excess acetone was removed at 60-80 C and the residue was treated with 600 ml of water at room temperature. The organic layer was then distilled under reduced pressure to give dioxolane (3) as a colorless oil and then used as such in the next step.

[0112] A mixture composed of dioxolane 3 (1.0 mol), concentrated sulfuric acid (0.05 mol), methanol (500 ml), and water (500 ml) was heated to reflux with vigorous stirring for several hours. The resulting mixture was then cooled to 50 °C and neutralized with dilute sodium hydroxide solution. The oily organic mass was separated and dried under reduced pressure at 80-90 C for a few hours to give V. Recrystallization gave an analytically pure desired compound 4.

[0113] Example 2: 2R, 3R-(2'-(2',2',7',7'-Tetramethyl-5'-tricyclo[6.2.1,0 1 ' 6 ]undec-4'-enyl)propan-T-yl)-2,3,4-trihydroxy-butyl ether To alcohol 1 (10 mmol) in THF, under stirring and inert atmosphere, is successively added, at room temperature, triethylamine (11 mmol) and, dropwise so that the temperature does not exceed 25°C, mesyl chloride (11 mmol). After one hour of reaction, the reaction medium containing product 5 is slowly added at -10°C to (-)-2,3-isopropylidene-D-threitol 1 (10 mmol) in solution in THF, which has previously deprotonated at -10°C, by addition of n-butyllithium (1M in hexane, 10 mmol). After the addition, the reaction medium is warmed to room temperature and left under stirring and inert atmosphere for 3 hours. After hydrolysis, the crude product is extracted with ethyl acetate. The combined organic phases are dried over MgSO4, filtered and condensed under vacuum. Product 6 is then purified by silica gel chromatography.

[0114] A mixture composed of dioxolane 6 (1.0 mol), concentrated sulfuric acid (0.05 mol), methanol (500 ml) and water (500 ml) was heated to reflux with vigorous stirring for several hours. The resulting mixture was then cooled to 50 °C and neutralized with dilute sodium hydroxide solution. The oily organic mass was separated and dried under reduced pressure at 80-90 C for a few hours to give the product 7 which was recrystallized from ethanol. Recrystallization gave an analytically pure desired compound 7.

[0115] Compound 8 is also obtained according to the same protocol [Table 2]

[0116] Example 3: 2'-(2',2',7',7'-Tetramethyl-5'-tricyclo [6.2.1,0 1 ' 6 ]undec-4'-enyl)propan-T-yl)- 2,3,4,5,6-pentahydroxy-cyclohexyl ether, mixture of isomers

[0117] To alcohol 1 (10 mmol) in THF, under stirring and inert atmosphere, is successively added, at room temperature, triethylamine (11 mmol) and, dropwise so that the temperature does not exceed 25°C, mesyl chloride (11 mmol). After one hour of reaction, the reaction medium containing product 5 is slowly added at -10°C to inositol (10 mmol) in solution in THF. After the addition, the reaction medium is warmed to room temperature and left under stirring and inert atmosphere for 3 hours. After hydrolysis, the crude product is extracted with ethyl acetate. The combined organic phases are dried over MgSO4, filtered and condensed under vacuum. Product 9 is then purified by chromatography on silica gel.

[0118] [Table 3]

[0119] Example 4: (2-(2,2,7,7-Tetramethyl-5-tricyclo[6.2.1.0 1 ' 6 ]undec-4-enyl)propan-1 -yl)-beta-D- glucopyranoside Ambermax 50, compound 1 (50%, 12.0 g, 22.9 mmol, 2 eq.) was dissolved in ethyl ether and washed 4 times with water, then dried (IX^SC ), filtered and concentrated. The residue was dissolved in dry dichloromethane (DCM) (30 mL) under an inert atmosphere, the solution was cooled to 0 °C and then 0-D-glucose pentaacetate (4.46 g, 11.43 mmol, 1.0 eq.) was added, followed by BF3.Et2O (2.8 mL, 22.7 mmol, 2.0 eq.) dropwise. The reaction mixture was left at room temperature, stirred for 5 hours and then hydrolyzed by the addition of saturated aqueous NaHCOs solution. The layers were separated and the organic layer was dried (IX^SCU), filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent Petroleum ether / Ethyl acetate 100:0 to 0:100) to give compound 15 (cis / trans mixture contaminated with deacetylated derivatives) as a colorless oil which was used as such in the next step.Compound 1 was dissolved in a solution of ammonia in methanol (7N in MeOH, 30 mL, 210 mmol, 18.3 eq.) and the reaction mixture was stirred for 48 h and then concentrated. The residue was purified by two successive flash column chromatographies on silica gel (eluent DCM / MeOH 100:0 to 80:20 then 100:0 to 90:10), and the impure fraction by a final flash column chromatography (eluent DCM / MeOH 100:0 to 90:10). All clean fractions were combined to provide compound 10 (cis / trans mixture, 2.10 g, 4.95 mmol, 43% in 2 steps) as a white solid. This is 2-(2,2,7,7-Tetramethyl-5-tricyclo[6.2.1.01,6]undec-4-enyl)propan-1 - yl)-beta-D-Glucopyranoside.

[0120] MS (ESI) m / z calcd. for C24H40O6 [M+Na] + 447.2; found 447.2. m / z calcd. C24H40O6 [M+HCOO]-469.3; found 469.2.

[0121] Compounds synthesized using this synthetic route

[0122] Similar syntheses are performed with alpha-L-fucopyranose triacetate, D-ribofuranose tetraacetate, beta-D-Galactopyranose pentaacetate or alpha-D-Mannopyranose pentaacetate instead of pD-glucose pentaacetate, according to the protocol described above.

[0123] The molecules obtained are referenced in the following table:

[0124] [Table 4] a - Compound 4163-65-9

[0125] Step 1: In a round-bottomed flask, under a nitrogen atmosphere, to a solution of Ambermax (1.34 g,

[0126] 5.12 mmol, 2eq) and per-O-acetyl-aD-mannopyranose (1.00 g, 2.56 mmol, 1 eq) in dichloromethane (7.70 mL) was added dropwise boron trifluoride diethyl ether (632 μL, 5.12 mmol, 2eq) at room temperature. The reaction mixture was stirred at room temperature for 18 hours, then boron trifluoride diethyl etherate (235 μL, 1.91 mmol, 0.4eq) was added. The reaction mixture was stirred at room temperature for 3 hours and then quenched by the addition of saturated aqueous NaHCOs solution (20 mL). The resulting mixture was extracted with dichloromethane (2*15 mL). The combined organic layers were washed with water, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent PE / EA, 100 / 0->0 / 100). Fractions containing the expected product were combined and concentrated to dryness, yielding a white solid (273 mg, 70%).

[0127] Step 2:

[0128] In a round-bottom flask under nitrogen atmosphere, sodium methoxide (10.5 pL, 46.1 pmol, 0.1 eq) was added to a solution of the product from step 1 (273 mg, 461 pmol, 1 eq) in MeOH (2.30 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then acetic acid (2.64 pL, 46.1 pmol, 0.1 eq) was added. The reaction mixture was stirred at room temperature for 10 minutes and concentrated, resulting in a white foam. The residue was purified by flash chromatography on silica gel (eluent of DCM / (DCM / MeOH 9 / 1) 100 / 0->0 / 100). Fractions containing the expected product were combined and concentrated to dryness, yielding a clear solid. The product was dissolved in a minimum of acetonitrile and water was added dropwise until precipitation. The mixture was stirred at room temperature for 17 h, then filtered through a Buchner funnel, yielding a white powder (149 mg, 76%).

[0129] 1 H NMR (DMSO-d6) 5 4.71-4.69 (m, 0.6 H), 4.67-4.58 (m, 1 .2 H), 4.55-4.48 (m, 1 .5 H), 4.44- 4.35 (m, 0.8 H), 3.68-3.50 (m, 3.0 H), 3.49-3.25 (m, 22.8 H), 3.22-3. 08 (m, 1.0 H), 3.00-2.88 (m, 1.0 H), 1.90-1.55 (m, 4.9 H), 1.44-1.30 (m, 3 H), 1.26-1.15 (m, 4.8 H), 1.14-0.98 (m, 4.0 H), 0.97-0.86 (m, 5.8 H), 0.84-0.77 (m, 2.8 H).

[0130] MS (ESI) m / z calculé, pour C24H4o06Na [M+Na]+ 447.3 ; trouvé 447.2 ; calculé pour C25H41O8 [M+HCOO]- 469.3 ; trouvé 469.2. b - Composé 4163-60-4

[0131] Etape 1 :

[0132] In a round-bottomed flask under nitrogen atmosphere, to a solution of Ambermax (1.34 g, 5.12 mmol, 2 eq) and pD-galactose peracetate (1.00 g, 2.56 mmol, 1 eq) (previously weighed together and coevaporated with 10 mL of toluene) in dichloromethane (7.70 mL) was added dropwise boron trifluoride diethyl etherate (632 μL, 5.12 mmol, 2 eq) at room temperature. The reaction mixture (transparent then transparent green) was stirred at room temperature for 18 h. The reaction mixture was quenched by the addition of saturated aqueous NaHcos solution at room temperature (15 mL). The resulting mixture was extracted with dichloromethane (2 * 15 mL). The combined organic layers were washed with water, dried over Na2SC>4, filtered, and concentrated to dryness to yield a yellow oil. The residue was purified by flash chromatography on silica (eluent PE / EA, 100 / 0->0 / 100).Fractions containing the expected product were combined and concentrated to dryness, yielding a pale yellow oil (1.06 g, 70%).

[0133] Step 2:

[0134] In a round-bottom flask under nitrogen atmosphere, sodium methoxide (41.0 μL, 179 pmol, 0.1 eq) was added to a solution of the product from step 1 (1.06 g, 1.79 mmol, 1 eq) in MeOH (9.00 mL) at room temperature. The reaction mixture (clear) was stirred at room temperature for 30 minutes. After 30 minutes, acetic acid (10.2 μL, 179 pmol, 0.1 eq) was added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and concentrated, resulting in a white foam. The residue was purified by flash chromatography on silica (DCM / (DCM / MeOH 9 / 1 eluent), 100 / 0->0 / 100). The fractions containing the expected product were combined and concentrated to dryness, yielding a transparent solid. The product was dissolved in acetonitrile and water was added dropwise until precipitation.The mixture was stirred at room temperature for 17 h, then filtered through a Buchner funnel, yielding a white powder (497 mg, 65%).

[0135] 1 H NMR {DMSO-do) 5 4.72-4.69 (m, 0.45 H), 4.69-4.59 (m, 0.96 H), 4.58-4.50 (m, 0.90 H), 4.37-4.28 (m, 0.77 H), 4.10-3.98 (m, 0.80 H), 3.67-3.40 (m, 3.82 H), 3.40-3.21 (m, 50.21 H), 3.04-2.84 (m, 1.00 H), 1.94-1.83 (m, 0.92 H), 1.78-1.56 (m, 3.58 H), 1.46-1.27 (m, 2.79 H), 1 .26- 1.15 (m, 4.58 H), 1.15-0.94 (m, 6.34 H), 0.94-0.86 (m, 2.65 H), 0.85-0.77 (m,2.55) MS (ESI) m / z calculated, for C24H4o06Na [M+Na] + 447.3; found 447.2; calculated, for C25H41O8 [M+HCOO]- 469.3; found 469.2. c - Compound 28078-32-9

[0136] Step 1:

[0137] In a round-bottom flask under nitrogen atmosphere, to a solution of pD-ribofuranose 1,2,3,5-tetraacetate (1.00 g, 3.14 mmol, 1 eq) and Ambermax (1.65 g, 6.28 mmol, 2 eq) in dichloromethane (9.44 mL) was added dropwise boron trifluoride diethyl ether (776 μL, 6.28 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCOs solution at room temperature (20 mL). The resulting mixture was extracted with dichloromethane (2 * 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to dryness, resulting in a yellow liquid. The residue was purified by flash chromatography on silica (PE / EA eluent, 100 / 0->0 / 100). The fractions containing the expected product were combined and concentrated to dryness, giving a pale yellow oil (911 mg, 56%).

[0138] Step 2:

[0139] In a round-bottom flask under nitrogen atmosphere, sodium methoxide (40.0 μL, 175 pmol, 0.1 eq) was added to a solution of the product from step 1 (911 mg, 1.75 mmol, 1 eq) in MeOH (8.74 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes, then acetic acid (10.0 μL, 175 pmol, 0.1 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and concentrated to give a yellow foam. The residue was purified by flash chromatography on silica (DCM / (DCM / MeOH 9 / 1 eluent), 100 / 0->0 / 100). The fractions containing the expected product were combined and concentrated to dryness, giving a yellow oil. The product was taken up in an ACN / H2O mixture (3 / 7) and lyophilized. (630 mg, 91%)

[0140] 1H NMR (DMSO-dQ) 5 4.98-4.87 (m,1.00 H), 4.86-4.74 (m, 1.22 H), 4.74-4.61 (m, 1.32 H), 4.61 -4.50 (m, 0. 99 H), 4.48-4.42 (m, 0.25 H), 3.85-3.68 (m, 2.94 H), 3.67-3.58 (m, 0.96 H), 3.58-3.45 (m, 2.15 H), 3. 45-3.38 (m, 0.65 H), 3.37-3.20 (m, 23.40 H), 3.17-3.03 (m, 1.03 H), 2.99-2.82 (m, 1.27 H), 1.92-1. 48 (m, 6.44 H), 1.48-1.25 (m, 3.80 H), 1.26-1.12 (m, 5.92 H),1 .12-0.83 (m, 12.59 H), 0.83-0.73 (m, 3.50 H)

[0141] MS (ESI) m / z calculé pour C23H 38 O5Na [M+Na] + 417,3 ; trouvé 417,2 ; calculé pour C24H39O7 [M+HCOO]- 439,3 ; trouvé 439,2. d - Composé 64913-16-2

[0142] Etape 1 :

[0143] In a round-bottom flask under nitrogen atmosphere, to a solution of 1,2,3,4-tetra-O-acetyl-α-L-fucopyranose (1.00 g, 3.01 mmol, 1 eq) and Ambermax (1.58 g, 6.02 mmol, 2 eq) in dichloromethane (9.04 mL) was added dropwise boron trifluoride diethyl ether (743 μL, 6.02 mmol, 2 eq) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCOs solution at room temperature (30 mL). The resulting mixture was extracted with dichloromethane (3*20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness, yielding a yellow liquid. The residue was purified by flash chromatography on silica ((Eluent of PE / EA, 100 / 0->0 / 100). Fractions containing the expected product were combined and concentrated to dryness, yielding a colorless oil (283 mg, 18%).

[0144] Step 2:

[0145] In a round-bottom flask under nitrogen atmosphere, sodium methoxide (12.1 pL, 52.9 pmol, 0.1 eq) was added to a solution of the product from step 1 (283 mg, 529 pmol, 1 eq) in MeOH (2.64 mL) at room temperature. The reaction mixture was stirred at room temperature for 35 minutes, then acetic acid (3.03 pL, 52.9 pmol, 0.1 eq) was added at room temperature. The reaction mixture was stirred at room temperature for 10 minutes and concentrated, resulting in a white foam. The residue was purified by flash chromatography on silica (DCM / (DCM / MeOH 9 / 1) eluent, 100 / 0->0 / 100). Fractions containing the expected product were combined and concentrated to dryness, yielding a white powder (191 mg, 99%).

[0146] 1H NMR DMSO-do) 5 4.71-4.53 (m, 1.00 H), 4.42-4.33 (m, 0.53 H), 4.12-3.94 (m, 0.97 H), 3.65-3.52 (m, 0.88 H), 3.53-3.43 (m, 0.98 H), 3.43-3.18 (m, 7.43 H), 3.07-2.88 (m, 0. 98 H), 1.97-1.82 (m, 1.06 H), 1.79-1.54 (m, 4.01 H), 1.50-1.25 (m, 3.11 H), 1.25-1.15 (m, 4.88 H), 1.16-0.94 (m, 10.09 H), 0.94-0.85 (m, 3.04 H), 0.84-0.76 (m, 2.82 H).

[0147] MS (ESI) m / z calculated for C24H 40 O5Na [M+Na] + 431.3; found 431.2; calculated for C25H41O7 [M+HCOO]- 453.3; found 453.2.

[0148] Example 5: Synthesis of the methylated derivative of Ambermax

[0149] A solution of Ambermax 1 (1g, 3.8 mmol) in DMF (5 mL) is added dropwise, at room temperature and under an inert atmosphere, to a solution of sodium hydride (0.27g or 5.6 mmol of a 50% by weight dispersion in mineral oil, washed times with anhydrous hexane) in THF (8 mL). After stirring for 3 hours at room temperature, methyl iodide (1.6g, 11 mmol) is added dropwise and under cooling in an ice bath so that the temperature does not exceed room temperature, then the reaction mixture is left stirring at room temperature for a further 4 hours. The reaction mixture is then poured onto an ice-cold solution of hydrochloric acid (2M, 100 mL) and the product is extracted with methyl-tert-butyl ether (2x100 mL).The combined organic phases are washed with saline solution (2x50ml) then dried (MgSO4), filtered, condensed under reduced pressure then purified by flash chromatography on silica gel to yield the desired compound 5-(1-methoxyprop-2-yl)-2,2,7,7-tetramethyltricyclo[6.2.1]undec-5-ene (0.73g, 69% yield, colorless oil).

[0150] Example 6 - Synthesis of a methylated derivative of Ambermax described in the prior art

[0151] In a round-bottomed flask, to a solution of Ambermax (3.00 g, 11.40 mmol) in DMF (100 mL) was added 60% sodium hydride (914 mg, 22.8 mmol) at 0°C. The reaction mixture was stirred at 0°C for 20 min. After 20 min, iodomethane was added at 0°C and the reaction mixture was stirred at room temperature for 18 h. After 18 h, the reaction mixture was diluted with water and extracted with DCM. The organic phase was separated, dried over Na2SO4, filtered and concentrated. A yellow oil was obtained. Purification on Biotage, normal phase, silica deposition, eluent PE / (PE / EA 9 / 1) 100 / 0 to 0 / 100. The desired product was obtained after evaporation of the fractions. A colorless oil was obtained (no crystallization was observed). (2.35 g, 75% yield) The structure and ratio were confirmed by NMR. Only HPLC on total absorbance was observed for this product.

[0152] 1H NMR (DMSO-cfe) 5 5.44- 5.31 (m, 0.4 H), 3.26-3.10 (m, 4.7 H), 3.08-2.98 (t, 0.4 H), 2.98- 2.84 (m, 0.7 H), 2.44-2.32 (0.4 H), 2.1 1 -2.01 (1.0 H), 1.94-1.78 (3.8 H), 1.77-1.48 (3.8 H), 1.45-1.26 (2.7 H), 1.25-1.1 1 (4.1 H), 1.11 -0.94 (6.3 H), 0.93-0.81 (5.1 H), 0.81 -0.71 (3.0 H) HPLC water / ACN 0.1% formic aid: t=24.482 mns and 24.829 min Ex vivo test on skin explants of the compounds according to the invention

[0153] In order to measure the effect of the compounds according to the invention, these were tested on human skin explants according to the protocol described below and according to the schedule shown in figure no. 1.

[0154] 1 - Preparation of products and study planning

[0155] The 20mM "SS" stock solution was prepared in DMSO (Sigma, ref D2650) on day 0 and stored at room temperature during the ex vivo phase. The compound used in the context of the invention is the following compound, represented by its semi-developed formula:

[0156] Several solutions of the compound are prepared as follows:

[0157] P1 = compound at 10pM in the culture medium - final concentration of DMSO 0.5%.

[0158] P2 = compound at 30pM in the culture medium - final concentration of DMSO 0.5%.

[0159] P3 = compound at 100pM in the culture medium - final concentration of DMSO 0.5%.

[0160] Solutions P1, P2 and P3 were prepared extemporaneously in the culture medium, each day of treatment.

[0161] 2- Characteristics of the plasty 18 human skin explants with an average diameter of 11 mm (±1 mm) were prepared on an abdominoplasty from a 50-year-old Caucasian woman (reference P2868-AB50) with phototype III according to the Fitzpatrick skin color classification. The explants were maintained in survival in BEM culture medium (BIO-EC's Expiants Medium) at 37°C in a humid atmosphere of 5% CO2.

[0162] The study was performed on a biopsy obtained from surgical waste after written informed consent from the donor, in compliance with the Declaration of Helsinki and Article L.1243-4 of the French Public Health Code. The latter does not require prior authorization from an ethics committee for the collection and use of surgical waste.

[0163] 3- Distribution of explants

[0164] The explants were divided into 6 batches as follows:

[0165] [Table 5]

[0166] 4- Application of the product

[0167] The tested solutions P1, P2 and P3 were systematically applied at the concentration indicated previously on day 0 (DO), D2, D3, D6, D7 and D9. The control explants T received no treatment except for the renewal of the culture medium. The culture medium was completely renewed (2 mL per well) on D2, D3, D6, D7 and D9.

[0168] 5- UV irradiation

[0169] On days 0 (DO), D1, D2, D3, D6, D7 and D9, the culture media of the irradiated explants (explants from the "UV" batch) were completely renewed (2 mL per well) on D1, D3, D6, D7 and D9 with HBSS (Hank's Balanced Saline Solution; 1 mL per explant). The explants were then irradiated using a Vilber Lourmat RMX 3W LIV simulator with a dose of 2.25 J / cm 2of UVA (with 6-8% UVB) corresponding to 0.5 MED (minimal erythemal dose) on a DNA sample. At the end of LIV irradiation, the explants were replaced in 2 mL of BEM medium.

[0170] 6- Sampling

[0171] At JO, the 3 explants from batch T0 were removed and cut into two parts. Half was fixed in a buffered formalin solution and the other half was frozen at -80°C.

[0172] On D10, 3 explants from the affected batches were taken and treated in the same way as on D0.

[0173] According to the provisions mentioned in the study plan, the days of treatments, irradiations and sampling were adjusted to the working days calendar.

[0174] 7- Histological treatment

[0175] After fixation for 24 hours in buffered formalin, the samples were dehydrated and impregnated with paraffin using a Leica PEARL dehydrator. The samples were embedded using a Leica EG 1160 embedding station. 5 μm thick sections were cut using a Leica RM 2125 Minot microtome. The sections were mounted on histological glass slides. Microscopic observations were performed using a Leica DMLB, an Olympus BX43 or BX63. Images were digitized using an Olympus DP72 or DP74 digital camera with cellSens storage software (Olympus).

[0176] 8- Cell viability

[0177] Cell viability of epidermal and dermal structures was assessed by microscopic observation of formalin-fixed, paraffin-embedded (FFPE) skin sections after staining with Masson's trichrome, Goldner variant.

[0178] 9- Visualization of melanin

[0179] Melanin was visualized after silver impregnation using the Masson Fontana staining method on FFPE skin sections. Staining was assessed by microscopic observation and semi-quantified by image analysis using cellSoft software or by image analysis using cellSens software (Olympus).

[0180] 10- Tyrosinase immunostaining Tyrosinase immunostaining was performed on FFPE skin sections with an anti-TRP-1 monoclonal antibody (Santa Cruz, ref. sc-20035) diluted 1:50 in PBS, 0.3% BSA overnight at room temperature, with a biotin / streptavavin amplification system, and revealed by VIP (Vector, ref. SK-4600), a peroxidase substrate giving a purple coloration once oxidized. The number of tyrosinase-positive cells is counted on each explant and expressed per cm of epidermis.

[0181] Results

[0182] 1. Cell viability

[0183] Cell viability of all batches is shown below:

[0184] [Table 6]

[0185] At JO, on the virgin batch T0, cell viability is good in the epidermis and good in the dermis.

[0186] At D10, on the EJ10 excipient batch, cell viability is quite good in the epidermis and good in the dermis.

[0187] After chronic UVA irradiation (UVJ10), cell viability is very slightly altered in the epidermis and good in the dermis.

[0188] Effect of products on cell viability expression, compared to batch EJ10:

[0189] • Product P1 does not induce any modification

[0190] • Product P2 does not induce any modification

[0191] • Product P3 does not induce any modification 2. Melanin

[0192] The visualization of melanin in the basal layer of the epidermis in all batches is shown in Figure 2.

[0193] At JO, on the virgin batch TO, the melanin coloration is clear in the basal layer of the epidermis.

[0194] At D10, on batch EJ10, the melanin content is moderate to fairly light in the basal layer of the epidermis.

[0195] UV-A irradiation (UVJ10 vs EJ10) induces a moderate increase in melanin content in the basal layer of the epidermis.

[0196] Effect of products on melanin content, compared to batch EJ10:

[0197] • Product P1 induces a slight increase

[0198] • Product P2 induces a moderate increase

[0199] • Product P3 induces a fairly clear increase

[0200] 3. Melanin Image Analysis

[0201] The percentage of area positive for melanin staining in the basal layer of the epidermis is shown below and in Figure 3:

[0202] [Table 7]

[0203] Melanin in the basal layer (% area)

[0204] At JO, on the control batch T0, the melanin coloration represents 45.6% of the surface of the basal layer of the epidermis.

[0205] At D10, on batch EJ10, melanin represents 16.9% of the surface area of ​​the basal layer of the epidermis.

[0206] UV irradiation (UVJ10 vs EJ10) induces a significant increase of 56%** in the melanin content of the basal layer of the epidermis.

[0207] The effect of the product at different concentrations on the melanin content, compared to batch EJ10: • Product P1 induces a significant increase of 41%**

[0208] • Product P2 induces a significant increase of 56% **

[0209] • Product P3 induces a significant increase of 109% **

[0210] **: p-value less than 0.01.

[0211] 4. Quantification of Tyrosinase

[0212] The number of tyrosinase-positive cells in the epidermis for all batches is shown below and in Figure 4:

[0213] [Table 8]

[0214] Number of tyrosinase-positive cells / cm of epidermis

[0215] At JO, on the virgin batch TO, the epidermis contains 152 cells (per cm) positive for tyrosinase immunostaining.

[0216] At D10, in batch EJ10, the epidermis contains 48 cells (per cm) positive for tyrosinase immunostaining.

[0217] UVA irradiation (UVJ10 vs EJ10) induces a significant increase of 91%* in tyrosinase-positive cells per cm of epidermis.

[0218] The effects of product application on tyrosinase-positive cells per cm of epidermis compared to batch EJ10 are:

[0219] • Product P1 induces a significant increase of 75%**

[0220] • Product P2 induces a significant increase of 74%**

[0221] • Product P3 induces a significant increase of 75%**

[0222] **: p-value less than 0.01.

[0223] The compound is well tolerated by human skin in ex vivo explants, regardless of concentration. It exhibits good pigment activity, superior at its highest concentration to that obtained after intense UV exposure, inducing a significant increase in melanin content and tyrosinase-positive cells after 10 days of treatment. Ex vivo test on melanocytes of the compounds according to the invention

[0224] Human skin pigmentation is due to the synthesis of melanin and its distribution in the skin and hair follicles. The process of melanogenesis is initiated in melanocytes, and more specifically in melanosomes, which are membrane-bound organelles linked to lysosomes.

[0225] Melanin plays a vital role in skin tone evenness and photoprotection against UV-induced DNA damage. Melanin production can be increased by internal factors (inflammatory or hormonal reactions) or external factors (sun exposure). This increased melanin production can lead to pigment damage or hyperpigmentation (age spots, melasma, acne lesions, etc.), which require skin care treatments.

[0226] In the present study, the effect of the compounds according to the invention was evaluated on melanin synthesis in melanocytes of normal human lightly pigmented epidermis (NHEM-LP) under L-tyrosine-stimulated conditions using photometric determination. Due to the nature of the compounds, a stimulating effect was expected.

[0227] Two incubation times were performed: 72 hours (3 days) and 216 hours (9 days). Indeed, according to the study sponsor's internal data, some of the compounds having a very strong potential effect on the stimulation of melanin synthesis could induce some toxicity due to melanin overload. Therefore, one experiment was interrupted after only 72 hours of incubation.

[0228] MATERIALS AND METHODS

[0229] - Biological model

[0230] - Cell type: Normal human epidermal melanocytes, lightly pigmented (NHEM-LP), QIMA Bioalternatives, reference: NHEM-2, used at passages 8, 9 and 12.

[0231] - Growing conditions: 37°C, 5% CO2

[0232] - Culture medium: Dermalife basal medium optimized for the test, supplemented with Dermalife M Lifefactors®.

[0233] CULTURE AND PROCESSING

[0234] Melanocytes were seeded in 24-well plates and cultured for 24 hours in culture medium. The medium was then replaced with culture medium containing or not (control) the tested compounds or the potential reference (IBMX tested at 200 pM), as well as the inducer (L-tyrosine, tested at 100 pM). In parallel, an unstimulated control was performed. The cells were then incubated for 3 days or 9 days with treatment renewals after 2 and 5 days.

[0235] All experimental conditions were carried out in triplicate.

[0236] Melanin content assessment

[0237] At the end of the incubation, culture supernatants were collected and melanin was extracted by cell lysis using 0.5 N NaOH solution. Optical density (OD) was then measured at 405 nm on both culture supernatants and in cell lysates, and the amount of melanin was determined according to a melanin standard curve ranging from 0.39 to 100 pg / ml, using a microplate reader (VERSAmax, Molecular Devices). Results were expressed as pg / ml of melanin and as % of the stimulated control.

[0238] Data management

[0239] Raw data were analyzed using Microsoft Excel® software.

[0240] Comparisons between groups were performed using an unpaired Student's t-test. Statistical analysis can be interpreted if n>5, but for n<5, statistical values ​​are given for informational purposes only.

[0241] Formula used in this report:

[0242] Standard error of the mean: sem = SD / n

[0243] The standard error of the mean (sem) is a measure of how far the sample mean is likely to be from the true population mean. It is calculated by dividing the standard deviation by the square root of the sample size.

[0244] RESULTS

[0245] First two series of experiments 72 hours of incubation

[0246] The data are grouped in the following Table 9 [Table 9]

[0247] After 72 hours of incubation, stimulation of melanocytes with 100 pM L-tyrosine induced a slight increase in intracellular melanin (11.6 pg / ml versus 8.9 pg / ml) and treatment of these stimulated melanocytes with 200 pM Ambermax did not significantly modulate their melanin content (extracellular and intracellular content).

[0248] Treatment of L-tyrosine-stimulated melanocytes with the following compounds induced a huge release of melanin into the supernatants: KOKU-0014, KOKU-0016, KOKU-0017 and KOKU-0018 with more than 2000% of the stimulated control at the highest concentration. This strong release of melanin was associated with a strong decrease in intracellular melanin content (up to 35% of the stimulated control). 3.1.2. 216 hours of incubation

[0249] [Table 10] After 216 hours of incubation, stimulation of melanocytes with 100 pM L-tyrosine induced an increase in melanin release into culture supernatants (4.8 pg / ml vs. 2.6 pg / ml), whereas no effect could be observed in the intracellular melanin content. Treatment of these L-tyrosine-stimulated melanocytes with 200 pM IBMX induced an accumulation of melanin in the intracellular compartment, whereas a decrease in melanin release into the supernatants was observed (190% and 60% of the stimulated control).

[0250] Treatment of L-tyrosine-stimulated melanocytes with the lowest concentrations of the following compounds induced an increase in melanin release in KOKU-0014, KOKU-0016, KOKU-0017, and KOKU-0018 supernatants up to -400% of the stimulated control. This melanin release was associated with a strong decrease in intracellular melanin content (up to 23% of the stimulated control). CONCLUSION

[0251] Under the experimental conditions of the study, all compounds induced an increase in the release of melanin into the extracellular compartment associated with a decrease in the amount of intracellular melanin.

Claims

Claims 1. Compound of the following formula I: or one of its enantiomers, isomers or diastereoisomers, or a mixture thereof, where R is a linear or cyclic C3-C6 alkyl comprising two hydroxyl functions, a linear or cyclic C3-C6 aldehyde comprising two hydroxyl functions, or a linear or cyclic C3-C6 ketone comprising two hydroxyl functions, and where R1 is a C1-C3 alkyl, or a salt, or a solvate thereof.

2. Compound according to claim 1, wherein said compound is chosen from the compound of formula Ia, Ib, Ic, Id, Ic, If, Ig and Ih, following: where R is as defined in claim 3. A compound according to claim 1 or 2, where R is a linear or cyclic C3-C6 alkyl comprising three hydroxyl functions, a linear or cyclic C3-C6 aldehyde comprising three hydroxyl functions, or a linear or cyclic C3-C6 ketone comprising three hydroxyl functions.

4. A compound according to any one of claims 1 to 2, where R is glycerol, 5. Compound according to any one of claims 1 to 3, where R is butane-1,2,3,4-tetrol, inositol, sorbitol or a C3-C6 sugar.

6. Compound according to any one of claims 1 to 5, said compound being chosen from the following compounds:

7. A compound according to claim 5, wherein said C3-C6 sugar is substituted with a C3-C6 sugar.

8. Compound according to claim 7, said compound being chosen from the following compounds:

9. Composition comprising a compound as defined in any one of claims 1 to 8, in association with a pharmaceutically or cosmetically acceptable vehicle.

10. Compound according to any one of claims 1 to 8, as a medicament.

11. Compound according to any one of claims 1 to 8, for its use in protecting the human epidermis against damage caused by ultraviolet radiation.

12. Compound according to any one of claims 1 to 8, for its use for the pigmentation of the skin, in particular lightly pigmented or depigmented skin.

13. Non-therapeutic cosmetic use of a compound according to any one of claims 1 to 8, for the pigmentation of the appendages, in particular in the absence of sun.

14. Non-therapeutic cosmetic use according to claim 13, where the appendages are the skin and the hair.

Images